Design, synthesis and biological evaluation of novel substituted purine isosters as EGFR kinase inhibitors, with promising pharmacokinetic profile and in vivo efficacy.

Abstract

Novel substituted purine isosters, were designed and synthesized as potential inhibitors of the Epidermal Growth Factor Receptor (EGFR). The compounds were rationally designed through bioisosteric replacement of the central quinazoline core of lapatinib, an approved drug that inhibits both EGFR and HER2, another important member of this family of receptors. The new target molecules were evaluated as inhibitors of receptor phosphorylation at the cellular level, for their direct inhibitory action on the intracellular receptor kinase domain and for their cytotoxicity against the non-small cell lung cancer cell line A549 and breast cancer HCC1954, cell lines which are associated with overexpression of EGFR and HER2, respectively. The most potent derivatives were further studied for their cellular uptake levels and in vivo pharmacokinetic properties. One compound (23) displayed a noteworthy pharmacokinetic profile, and higher intracellular accumulation in comparison to lapatinib in the A549 cells, possibly due to its higher lipophilicity. This lead compound (23) was assessed for its efficacy in an EGFR positive xenograft model, where it successfully inhibited tumor growth, with a similar efficacy with that of lapatinib and with minimal phenotypic toxicity.

• Authors: Efthymios-Spyridon Gavriil, Aris Doukatas, Theodoros Karampelas, Vassilios Myrianthopoulos, Spyridon Dimitrakis, Emmanuel Mikros, Panagiotis Marakos, Constantin Tamvakopoulos, Nicole Pouli
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 176 Pg. 393-409 (Aug 15 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 31125894 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Purines
• Lapatinib
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacokinetics, therapeutic use)
• Catalytic Domain
• Cell Line, Tumor
• Female
• Humans
• Lapatinib (analogs & derivatives, chemical synthesis, pharmacokinetics, therapeutic use)
• Male
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Molecular Docking Simulation
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacokinetics, therapeutic use)
• Purines (chemical synthesis, chemistry, pharmacokinetics, therapeutic use)
• Receptor, ErbB-2 (antagonists & inhibitors, chemistry)